JP2001521001A - Cyclic phosphonate ester inhibitors and methods of inhibiting microsomal triglyceride transfer proteins - Google Patents

Abstract

(57) Abstract The present invention provides novel cyclic phosphonate ester inhibitors of MTP that are useful for lowering serum cholesterol and triglycerides. The inhibitor of the present invention is represented by the following formula. Embedded image (Wherein, R ² , L ² , A, B, L ¹ , R ¹ and R ^5a have the same meaning as described in the specification)

Description

Description: TECHNICAL FIELD The present invention relates to a novel cyclic compound that inhibits microsomal triglyceride transfer protein
Phosphonate esters and serum lipid reduction and atheroses using such compounds
The present invention relates to a method for treating multiple sclerosis. BACKGROUND ART Microsomal triglyceride transfer protein (MTP) is a small unilamellar vesicle
(SUV) triglyceride (TG), cholesteryl ester (CE) and
Catalyzes the transport of phosphatidylcholine (PC) [Wetterau & Zilversmit
"Chem. Phys. Lipids" ( 38 , 205-222, 1985)]. Expressing the transfer rate as a percentage of the donor lipid transferred per hour, MTP is
A clear choice of neutral lipid transport (TG and CE) is shown for phospholipid transport.
Protein has been isolated and characterized from bovine liver [Wetterau & Zi
lversmit's "Chem. Phys. Lipids" ( 38 , 205-222, 1985)
reference]. The polyacrylamide gel electrophoresis analysis of the purified protein
The transfer protein is a complex of two subunits with apparent molecular weights of 58,000 and 88000.
It is suggested that purified MTP is electrophoresed under non-denaturing conditions.
Upon running, a single band was present, while electrophoresis was performed using sodium dodecyl sulfate (S
DS), two bands with apparent molecular weights of 58,000 and 88,000
Is identified. Hereinafter, these two polypeptides are referred to as 58k
Da and 88 kDa, or the 58 kDa and 88 kDa components of MTP,
Are referred to as low and high molecular weight subunits. [0003] The characterization of the 58,000 molecular weight component of bovine MTP has been previously characterized.
Multifunctional protein, ie, protein disulfide isomerase (PDI)
[Wetterau et al., J. Biol. Chem. 265 , 9800-98
07, 1990)]. The presence of PDI in the metastatic protein is due to (1) MTP
The amino-terminal 25 amino acids of the bovine 58000 kDa component are similar to those of bovine PDI.
And (2) the disulfide isomerase activity is 58 kDa-8
Shows that it is expressed by bovine MTP after dissociation of the 8 kDa protein complex
Supported by evidence. In addition, bovine PDI, ie, possesses TG transfer activity itself.
Antibodies raised against non-proteins were purified from solutions containing purified bovine MTP.
TG transfer activity could be immunoprecipitated. [0004] PDI is a form of newly synthesized disulfide-linked protein in the lumen of the stroma.
Plays a normal role in folding and assembly [Bu
lleid & Freedman 「Nature」 335 649-651, 1988). PDI is a suitable pairing of cysteine residues to disulfide bonds (
catalyze pairing). In addition, PDI has been reported to correspond to the beta subunit of human prolyl 4-hydroxylase [Koivu et al.
Biol. Chem. ”( 262 , 6447-6449, 1987)]. Cattle roll
The role of PDI in translocation is not clear. Low concentrations of denaturants (guanidine HC
l), PDI from the 88 kDa component of bovine MTP with either a chaotropic agent (sodium perchlorate) or a non-denaturing detergent (octyl glucoside)
PDI is an integral part of the metastatic protein because dissociation results in loss of metastatic activity.
[Wetterau et al., "Biochemistry" ( 30 , 9728-9735, 1991)]. The isolated bovine PDI has no apparent lipid transfer activity.
However, this does not indicate whether the 88 kDa polypeptide is a transposable protein.
Or suggest that it confers translocation activity on the protein complex. [0005] The distribution of MTP activity in tissues and cells in rats has been studied [Wette
rau &Zilversmit's"Biochem. Biophys. Acta" ( 875 , 610-6
17, 1986)]. Lipid transfer activity has been found in liver and intestine. plasma
Little or no metastatic activity in the brain, heart or kidney
. In the liver, MTP is a soluble protein located within the lumen of the microsomal fraction.
there were. Almost equal concentration in smooth and coarse microsomes
I understood. [0006] β-Lipoproteinemia is an autosomal recessive disease characterized by a substantial lack of plasma lipoproteins containing apolipoprotein B (apoB) [Kane & Havel, The Metabolic Basis of Inherited. Disease "(6th edition, 1139-1164, 1989)]. Plasma TG level is about several mg / dL
It can be low and does not increase after fat intake. Plasma cholesterol levels
Is often only 20-45 mg / dL. These abnormalities affect the liver
Very low density lipoprotein (VLDL) and intestinal chylomicron aggregation and / or
It is the result of a genetic defect in secretion. The molecular basis for this defect has been
Not determined in In the subjects examined, triglycerides, phospholipids,
And cholesterol synthesis appear to be normal. At autopsy, subject has atherosclerosis
No metaplasia [Schaefer et al., "Clin. Chem." 34 , B9-12, 1988.
Year)]. The association between the apoB gene and β-lipoproteinemia has been ruled out in some families [Talmud et al., J. Clin. Invest. 82 , 1803-18
06, 1988) and Huang et al., "Am. J. Hum. Genet." 46 , 1
141-1148, 1990)]. Subjects with abeta-lipoproteinemia suffer from a number of diseases [see Kane & Havel, supra]. The subject has fat malabsorption and TG accumulation in enterocytes and hepatocytes. Based on the lack of TG-rich plasma lipoproteins,
Defects in the transport of proteins (eg, vitamin E). This is a spiny red blood cell of red blood cells
Ataxia, pale cerebellar ataxia with thin wedge-shaped fiber bundle degeneration, peripheral neuropathy, degenerative pigmentedness
This leads to retinopathy, and celloid myopathy. Treatment of subjects without β-lipoproteinemia
Dietary restrictions on fat intake and dietary supplements of vitamins A, E and K
No. In vitro, MTP catalyzes the transport of lipid molecules between phospholipid membranes. Maybe M
TP plays several roles in lipid metabolism by playing the same role in vivo.
Will do. MTP subcellular (lumen of microsomal fraction) and tissue distribution (liver
And intestine) lead to the conclusion that MTP plays a role in the assembly of plasma lipoproteins.
However, the reason is that they are sites of plasma lipoprotein assembly [W
"Biochem. Biophys. Acta" by etterau & Zilversmit ( 875 , 610
-617, 1986)]. The ability of MTP to catalyze the transport of TG between membranes is
Consistent with this hypothesis, and MTP is located at the site of endoplasmic reticulum (ER) synthesis
Suggests that it can catalyze the transport of TG to lipoprotein particles that are about to evolve
I do. Olofsson and colleagues studied lipoprotein assembly in HepG2 cells
[Bostrom et al., J. Biol. Chem. 263 , 4434-4442, 1988)]. According to their results, the small precursor lipoprotein was large over time.
It is suggested to be. This happens because the lipid molecules aggregate,
Would be consistent with the addition or transfer of lipid molecules to the lipoprotein. Of this hypothesis
In support, Howell and Palade have isolated a lipoprotein that is about to develop from the liver Golgi fraction of rat liver [Howell and Palade, J. Cell. Biol. 92 833-845, 1982). There was a spectrum of particle size with varying lipid and protein composition. High density lipoprotein (HDL) particles containing apoB were found. Higgins and Hutson have reported that lipoproteins isolated from Golgi are consistently larger than those from the endoplasmic reticulum [Higgins and Hutson, J. Lipid Res. 25 , 1295-1305, 1984)].
Suggested that the assembly of lipoproteins was a progressive situation. However,
MTP plays a role in lipid metabolism or plasma lipoprotein assembly in the art
There is no straightforward evidence to prove. A recent report [“Science” (Vol. 258, p. 999, 1992); S
According to Harp et al., “Nature” (Vol. 365, p. 65, 1993)]
The defect causing lipoproteinemia is the MTP gene and consequently the MTP protein
It is proved that there is. Individuals with β-lipoproteinemia without MTP activity
And some of them have been characterized as a result of mutations in the MTP gene.
It is. These results indicate that the precursor to LDL, namely lipoproteins such as VLDL,
This shows that MTP is required for the synthesis of apoB. Therefore, inhibitors of MTP inhibit the synthesis of VLDL and LDL, thereby reducing VLD in animals and humans.
L, LDL, cholesterol, and triglyceride levels
Will be lowered. [0011] Canadian Patent Application No. 200991102 (issued on March 2, 1994) [Compare with US Patent Application No. 117362 (file DC21b) filed on September 3, 1993]
MTP inhibitors that block the production of apoB-containing lipoproteins in a human hepatocyte cell line (HepG2 cells) have been reported. This further implies that MTP inhibitors
Supports a proposal to reduce apoB-containing lipoprotein and lipid levels in vivo. This Canadian patent application has the formula: An MTP inhibitor named 2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-3-oxo-1H-isoindole hydrochloride;
Formula: 1- [3- (6-Fluoro-1-tetralanyl) methyl] -4-O-methoxy
A method for identifying an MTP inhibitor named nil piperazine is disclosed. EP0643057A1 (issued March 15, 1995) has the formula: , Including pharmaceutically acceptable salts and anions or esters thereof
An MTP inhibitor is disclosed, wherein X is of the formulas I, II and III: R ⁸ , R ⁹ And R ^Ten Is each independently hydrogen, alkyl, alkenyl, al
Quinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl
, Cycloalkyl, or cycloalkylalkyl; Y is-(CH _Two m) or -CO-; m is 2 or 3; R ¹ Is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl (where the alkyl has at least 2 carbon atoms), diarylalkyl
, Arylalkenyl, diarylalkenyl, arylalkynyl, diary
Rualkynyl, diarylalkylaryl, heteroarylalkyl (where
, Alkyl having at least 2) carbon atoms, cycloalkyl, or cycloalkyl
Alkyl (where the alkyl has at least 2 carbon atoms) ¹ All of the groups may be optionally substituted through an available carbon atom, halo, haloalkyl, alkyl, alk
Kenyl, alkoxy, aryloxy, aryl, arylalkyl, alkyl
Melpt, arylmercapto, cycloalkyl, cycloalkylalkyl, f
Teloaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo
R may be substituted with one, two or three groups selected from ¹ Is of the formula: A group of R ¹¹ Is a bond, alkylene, alkenylene or alkynylene having 6 or less carbon atoms
, Arylene (for example, ) Or an arylene-alkylene mixture (for example, N is 1 to 6; R ¹² Is hydrogen, alkyl, alkenyl, aryl, heteroaryl, haloalkyl
, Arylalkyl, arylalkenyl, cycloalkyl, aryloxy
, Alkoxy, arylalkoxy, heteroarylalkyl or cycloal
Z is a bond, O, S, N-alkyl, N-aryl, or C 1-5 alkyl.
Alkylene or alkenylene; R ¹³ , R ¹⁴ , R ^Fifteen And R ¹⁶ Is each independently hydrogen, alkyl, halo, ha
Loalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl,
Alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfo
Nil, arylsulfonyl, alkylthio, arylthio, carboxy, amino
Carbonyl, alkylcarbonyloxy, alkylcarbonylamino, aryl
Alkyl, heteroaryl, heteroarylalkyl, or aryloxy;
Or R ¹ Is , Where p is 1 to 8, R ¹⁷ And R ¹⁸ Is independently H, alkyl, a
Lucenyl, aryl, arylalkyl, heteroaryl, heteroarylal
Kill, cycloalkyl or cycloalkylalkyl, provided that R ¹⁷ And R ¹⁸ Few
At least one is other than H; or R ¹ Is , Where R ¹⁹ Is aryl or heteroaryl, R ²⁰ Is aryl or hetero
Aryl, R ^{twenty one} Is H, alkyl, aryl, alkylaryl, arylalkyl
, Aryloxy, arylalkoxy, heteroaryl, heteroaryl
Alkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl
Or cycloalkylalkoxy; R ^Two , R ^Three , R ^Four Are each independently hydrogen, halo, alkyl, haloalkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
Kill mercapto, aryl mercapto, cycloalkyl, cycloalkyl alk
, Heteroaryl, heteroarylalkyl, hydroxy or haloalkyl
R ^Five Is an alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl having at least 2 carbon atoms
, Cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl
, Cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, poly
Cycloalkenylalkyl, heteroarylcarbonyl, ^Five And R ⁶ All of the substituents may be hydrogen, halo, alkyl, ha, optionally through an available carbon atom.
Loalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloa
Alkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkyl
Alkyl, aryl, heteroaryl, arylalkyl, arylcycloa
Alkyl, arylalkynyl, aryloxy, aryloxyalkyl, ant
Alkoxy, arylazo, heteroaryloxo, heteroarylalkyl
, Heteroarylalkenyl, heteroaryloxy, hydroxy, nitro,
Cyano, amino, substituted amino (where amino is alkyl or aryl,
Or one or two substituents which are any of the other aryl compounds mentioned in the definition
), Thiol, alkylthio, arylthio, heteroarylthio, ant
Thioalkyl, alkylcarbonyl, arylcarbonyl, arylamino
Carbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocar
Bonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylca
Rubonyloxy, arylcarbonyloxy, alkylcarbonylamino, ant
Carbonylamino, arylsulfinyl, arylsulfinylalkyl
, Arylsulfonyl, alkylsulfonyl, arylsulfonylamino
And may be substituted with one, two or three groups, provided that R ^Five Is CH _Three When, R ⁶ Is not H, and R ^Five When phenyl is phenyl, the phenyl is preferably an ortho-hydrophobic substituent such as alkyl, haloalkyl, aryl, aryloxy or
Containing reel alkyl; R ⁶ Is hydrogen or C ₁ -C _Four Alkyl or C ₁ -C _Four Alkenyl; R ⁷ Is alkyl, aryl or arylalkyl, wherein the alkyl or alkyl moiety may be optionally substituted by oxo. In the above compound of formula I, X is CH _Two In R ^Two , R ^Three And R ^Four Is the place of H respectively
If R ¹ Is other than 3,3-diphenylpropyl. In the compound of formula III above, R ^Two , R ^Three And R ^Four Is one of 6-fluoro and the other two are H, R ⁷ Is other than 4-o-methoxyphenyl. US Patent Application No. 472067 (filed on June 6, 1995, file DC2
1e) has the formula: Embedded image Which is represented by Including N-oxides and pharmaceutically acceptable salts of
You. In the formula, Q is X is R ⁸ , R ⁹ And R ^Ten Is each independently hydrogen, alkyl, alkenyl, al
Quinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl
Y is cycloalkyl or cycloalkylalkyl; Y is Where m is 2 or 3; R ¹ Is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl (where the alkyl has at least 2 carbon atoms), diarylalkyl
, Arylalkenyl, diarylalkenyl, arylalkynyl, diary
Rualkynyl, diarylalkylaryl, heteroarylalkyl (where
, Alkyl having at least 2) carbon atoms, cycloalkyl, or cycloalkyl
Alkyl (here, alkyl has at least 2 carbon atoms), and all of these
Optionally through an available carbon atom, halo, haloalkyl, alkyl, alkenyl
, Alkoxy, aryloxy, aryl, arylalkyl, alkylmerca
Pt, arylmercapto, cycloalkyl, cycloalkylalkyl, hetero
Aryl, fluorenyl, heteroarylalkyl, hydroxy or oxo
R 1 may be substituted with one, two, three or four groups selected from ¹ Is of the formula: Embedded image A fluorenyl-type group; or R ¹ Is of the formula: An indenyl-type group of Z ¹ And Z ^Two Are the same or different and are each independently a bond, O, S, (Alkyl is translated as alkyl, the same applies hereinafter.) B With respect to Z ¹ And Z ^Two At least one is other than a bond; R ¹¹ Is a bond, alkylene, alkenylene or alkynyl having 10 or less carbon atoms
R, arylene or an arylene-alkylene mixture; R ¹² Is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloal
Kill, trihaloalkylalkyl, heteroaryl, heteroarylalkyl,
Arylalkyl, arylalkenyl, cycloalkyl, aryloxy, a
Alkoxy, arylalkoxy or cycloalkylalkyl, provided that (1) R ¹² Is H, aryloxy, alkoxy or arylalkoxy
Come, Z ^Two Is Or a bond, and (2) Z ^Two Is a bond, R ¹² Cannot be heteroaryl or heteroarylalkyl; Z is a bond, O, S, N-alkyl, N-aryl, or C 1-5 alkyl.
Alkylene or alkenylene; R ¹³ , R ¹⁴ , R ^Fifteen And R ¹⁶ Is each independently hydrogen, alkyl, halo, ha
Loalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl,
Alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfo
Nil, arylsulfonyl, alkylthio, arylthio, aminocarbonyl,
Alkylcarbonyloxy, arylcarbonylamino, alkylcarbonyla
Mino, arylalkyl, heteroaryl, heteroarylalkyl, or
Reeloxy; R ^15a And R ^16a Is independently hydrogen, alkyl, halo, haloalkyl
, Aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl
, Alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, ant
Thiol, aminocarbonyl, alkylcarbonyloxy, arylcarbonyl
Amino, alkylcarbonylamino, arylalkyl, heteroaryl, hete
Loarylalkyl or aryloxy; or R ¹ Is Where p is 1-8, R ¹⁷ And R ¹⁸ Is independently H, alkyl
, Alkenyl, aryl, arylalkyl, heteroaryl, heteroaryl
Alkyl, cycloalkyl or cycloalkylalkyl, ¹⁷ And R ¹⁸ Few
At least one other than H; or R ¹ Is Where R is ¹⁹ Is aryl or heteroaryl, R ²⁰ Is aryl or f
Teloaryl, R ^{twenty one} Is H, alkyl, aryl, alkylaryl, aryl
Alkyl, aryloxy, arylalkoxy, heteroaryl, heteroaryl
Alkyl, heteroarylalkoxy, cycloalkyl, cycloalkyl
Kill or cycloalkylalkoxy; R ^Two , R ^Three , R ^Four Are each independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto
, Arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl
R, heteroarylalkyl, hydroxy or haloalkyl; R ^Five Is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl,
Heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycl
Loalkyl, polycycloalkylalkyl, cycloalkenyl, cyclohetero
Alkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkene
Nil, polycycloalkenylalkyl, heteroarylcarbonyl, amino,
Alkylamino, arylamino, heteroarylamino, cycloalkyloxy
, Cycloalkylamino, all of which optionally have available carbon atoms
Through hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,
Alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloto
Heteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, a
Reel alkyl, arylcycloalkyl, arylalkenyl, arylal
Quinyl, aryloxy, aryloxyalkyl, arylalkoxy, ant
Azo, heteroaryl oxo, heteroaryl alkyl, heteroaryl
Lucenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted
Amino, thiol, alkylthio, arylthio, heteroarylthio, aryl
Luthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminoca
Rubonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbo
Nil, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarb
Bonyloxy, arylcarbonyloxy, alkylcarbonylamino, aryl
Carbonylamino, arylsulfinyl, arylsulfinylalkyl,
Arylsulfonyl, alkylsulfonyl, arylsulfonylamino, hetero
Arylcarbonylamino, heteroarylsulfinyl, heteroarylthio
, Heteroarylsulfonyl and alkylsulfinyl,
Or 4 groups; R ⁶ Is hydrogen or C ₁ -C _Four Alkyl or C ₁ -C _Four Alkenyl, all of which are optionally substituted with R ^Five R may be substituted with 1, 2, 3 or 4 groups which may be any of the substituents listed in the definition of R. ⁷ Is an alkyl, aryl or arylalkyl, wherein itself or some of the alkyls of the arylalkyl are optionally substituted with oxo (= O)
); Are the same or different and are each independently a heterocyclic group containing a 5- or 6-membered ring.
Selected from the group consisting of _Two In R ^Two , R ^Three And R ^Four Are both H, ¹ Is other than 3,3-diphenylpropyl, and in the fifth formula, R ^Two , R ^Three And R ^Four Is one of 6-fluoro and the other two are H, R ⁷ Is other than 4- (2-methoxyphenyl). U. S. Provisional application No. No. 60/017224 (filed on May 5, 1996)
Formula: embedded image And pharmaceutically acceptable salts thereof and compounds including N-oxides are disclosed.
Have been. In the above formulas I, IA and IB, q is 0, 1 or 2; A is (1) a bond, (2) —O—, or (3) , Where R ^Five Is H or lower alkyl, or R ^Five Is R ^Two Together form a 4-8 membered carbocyclic or heterocyclic ring group; B is of the formula: Or a fluorenyl-type group of the formula: An indenyl-type group of R ^X Is H, alkyl or aryl; R ¹ Is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl) _Three Si (where each alkyl or aryl is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkyl
Mino, aryl, arylalkyl, arylamino, aryloxy, hetero
Aryl, heteroarylamino, heteroaryloxy, arylsulfonyl
Amino, heteroarylsulfonylamino, arylthio, arylsulfini
, Arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfur
Honyl, heteroarylthio, heteroarylsulfinyl, heteroaryls
Ruphonyl, -PO (R ¹³ ) (R ¹⁴ ) (Where R ¹³ And R ¹⁴ Are independent
Alkyl, aryl, alkoxy, aryloxy, heteroaryl,
Loarylalkyl, heteroaryloxy, heteroarylalkoxy, cyclo
Roheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy
Or cycloheteroalkyl), aminocarbonyl (where amino is optional
May be substituted with one or two aryl, alkyl or heteroaryl groups
), Cyano, 1,1- (alkoxy or aryloxy) _Two Alkyl [where the two aryl or alkyl substitutions are separately independent or
L ¹ (Or R ^Two L for ^Two To form a ring connected to ¹ (Or R ^Two L for ^Two 1,3-dioxane or 1,3-dioxolane linked to ¹ The group may be optionally substituted with 1, 2, 3, or 4 substituents, such substituents being those described above for R ^Three Or R ¹ Any of the groups or
Alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonyl
Ruamino, heteroarylcarbonylamino, alkoxycarbonylamino,
Reeloxycarbonylamino, heteroaryloxycarbonylamino, urea
Where the ureido nitrogen is optionally alkyl, aryl or hetero
Optionally substituted with aryl), heterocyclic carbonylamino (where heterocyclic is nitrogen
Or linked to the carbonyl group via a carbon atom)
Mino, arylsulfonylamino, heteroarylsulfonylamino, Where J is R ^{twenty three} , R ^{twenty four} And R ^{twenty five} Is each independently hydrogen, alkyl, alkenyl, al
Quinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl
R, cycloalkyl or cycloalkylalkyl; R ²⁰ , R ^{twenty one} , R ^{twenty two} Is each independently hydrogen, halo, alkyl, alkenyl,
Alkoxy, aryloxy, aryl, arylalkyl, alkyl mercap
G, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroa
A reel, heteroarylalkyl, hydroxy or haloalkyl,
These substituents are R ¹ R or a bond via an alkylene in the open position; ^Two Is independently R ¹ Any of the groups H, polyhaloalkyl, or cyclo
A heteroalkyl, wherein R ^Two Is R ^Three Or the above R ¹ L may be substituted with 1 to 4 of the substituents defined in the case of ¹ Is a linking group containing from 1 to 10 carbons in a straight chain, including alkylene, alkenylene or alkynylene, wherein one or two alkenes in the linking chain;
It may contain one or two alkynes, oxygen, amino groups, oxo groups and
L may be substituted with 5 alkyl or halo groups; L ^Two Is the above L ¹ May be the same as or different from ^Two Is independently L ¹ Base
R or a single bond; R ^Three , R ^Three ', R ^Four And R ^Four 'Are the same or different and are each independently H
, Halogen, CF _Three , Haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alka
Noyl, nitro, amino, thiol, alkylthio, alkylsulfinyl,
Alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl,
Alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl,
Cycloheteroalkylalkyl, cyano, Ar-, Ar-alkyl, ArO, A
r-amino, Ar-thio, Ar-sulfinyl, A-sulfonyl, Ar-carbo
Nil, Ar-carbonyloxy or Ar-carbonylamino (where Ar-
Is aryl or heteroaryl, and Ar is optionally condensed to Ar
R 1, R 2, R 3, R 2, R 3, R 2, R 3, R 2, R 3, R 2, R 3 and R 2; ^3a And R ^3b Are the same or different and are each independently ^Three Any of the groups except for hydroxy, nitro, amino or thio; Are the same or different and each independently has 1, 2, 3 or 4
5- or 6-membered heteroatoms containing terror atoms (which, independently, are N, S or O)
X is a loaryl ring, including its N-oxide; X is a bond, or a compound of the formula: Wherein Y is O, NR ⁶ Or S; n ′ is 0, 1 or 2; R ⁶ Is H, lower alkyl, aryl, -C (O) -R ¹¹ Or —C (O) —O—R ¹¹ R ⁷ And R ⁸ Are the same or different and are each independently H, alkyl,
Reel, halogen or -OR ¹² Or R ⁷ And R ⁸ May together form oxygen to form a ketone; R ⁹ , R ^Ten , R ⁹ 'And R ^Ten 'Are the same or different and are each independently
H, lower alkyl, aryl or -OR ¹¹ R ⁹ "And R ^Ten "Are the same or different and are each independently H, lower alkyl, aryl, halogen or -OR. ¹¹ R ¹¹ Is alkyl or aryl; R ¹² Is H, alkyl or aryl, provided that the formula: (A) R ¹ Is unsubstituted alkyl or unsubstituted arylalkyl; ¹ Is Ami
(B) R ¹ Is an alkyl, ¹ Contains amino and oxo in adjacent positions
That is, an amide group cannot be formed). ^Two L ^Two A- is H _Two When N-, R ¹ L ¹ Cannot contain amino, and (d) R ¹ When is cyano, L ¹ Must have at least two carbons, and (e) R ¹ L ¹ Must contain at least 3 carbons; for compounds of Formulas I, IA and IB, R ¹ Is cycloheteroalkyl, R ¹ Excludes 1-piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1- (2-oxopyrrolidinyl); for compounds containing sulfur and alcohols, R ^Two L ^Two Is S = (O) q or
Is CR ^X Cannot have an O or N atom directly attached to (OH) and in the case of IA, R ^Two L ^Two Cannot be H. According to the present invention, there is provided an agent for inhibiting MTP, which is represented by the following formula I,
New salts, including chemically acceptable salts and stereoisomers and diastereomers
Compounds are provided. Embedded image In the formula, A represents (1) a bond, (2) —O—, or Where R ^Five Is H or lower alkyl, or R ^Five Is R ^Two Together form a 4-8 membered carbocyclic or heterocyclic ring group. B is the formula: (The B may be referred to as a fluorenyl-type ring or component.)
Or B is of the formula: An indenyl group (B may be referred to as an indenyl ring or component)
You. R ^a And R ^b Are the same or different and are hydrogen, alkyl, aryl, aryl
Alkyl or heteroaryl linked to the ring via a carbon atom. R ^5a Is H, lower alkyl or aryl. R ¹ Is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, heteroaryl
Coxy, arylalkyl, heteroarylalkyl, cycloalkyl, cyclo
Alkylalkyl, polycycloalkyl, polycycloalkylalkyl, cyclo
Alkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenyl
Alkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroaryl
Carbonyl, amino, alkylamino, arylamino, heteroaryl
Mino, cycloalkyloxy and cycloalkylamino;
Hydrogen, halo, alkyl, haloalkyl through an available carbon atom
, Alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl,
Cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl
, Aryl, heteroaryl, arylalkyl, arylcycloalkyl,
Arylalkenyl, arylalkynyl, aryloxy, aryloxya
Alkyl, arylalkoxy, arylazo, heteroaryloxo, heteroa
Reel alkyl, heteroarylalkenyl, heteroaryloxy, hydroxy
Si, nitro, cyano, amino, substituted amino, thiol, alkylthio, aryl
Thio, heteroarylthio, arylthioalkyl, alkylcarbonyl, ant
Carbonyl, arylaminocarbonyl, alkoxycarbonyl, aminoca
Rubonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenyl
Aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
Alkylcarbonylamino, arylcarbonylamino, arylsulfinyl
, Arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
Arylsulfonylamino, heteroarylcarbonylamino, heteroaryl
Sulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfur
May be substituted with one, two, three or four groups selected from finyl; ¹ And R ^5a Together form the formula: Wherein J is of the formula , R ^{twenty three} , R ^{twenty four} And R ^{twenty five} Is each independently hydrogen, alkyl, alkenyl, a
Ruquinyl, aryl, arylalkyl, heteroaryl, heteroaryl
Alkyl, cycloalkyl, or cycloalkylalkyl. R ²⁰ , R ^{twenty one} , R ^{twenty two} Is each independently hydrogen, halo, alkyl, alkenyl,
Alkoxy, aryloxy, aryl, arylalkyl, alkyl mercap
G, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroa
A reel, heteroarylalkyl, hydroxy or haloalkyl,
These substituents are R ¹ May be bonded directly or via an alkylene at the open position. R ^Two Is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, (alkyl or aryl) _Three Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino,
Substituted arylalkylamino, aryl, arylalkyl, arylamino,
Aryloxy, heteroaryl, heteroarylamino, heteroaryloxy
, Arylsulfonylamino, heteroarylsulfonylamino, arylthio
E, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfur
Finyl, alkylsulfonyl, heteroarylthio, heteroarylsulfy
Nil, heteroarylsulfonyl, cycloheteroalkyl, cycloheteroalkyl
Alkyl, -PO (R ¹³ ) (R ¹⁴ ) (Where R ¹³ And R ¹⁴ Are independent
And alkyl, aryl, alkoxy, aryloxy, heteroaryl,
Teloarylalkyl, heteroaryloxy, heteroarylalkoxy,
Cloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy
Or cycloheteroalkoxyalkyl), cyano, 1,1- (alkoxy or
Or aryloxy) _Two Alkyl (where the two aryl or alkyl substituents may be independently defined). Also, R ^Two The group is optionally substituted with the above R ¹ Any of the substituents, and preferred below
R ^Two It may have from 1 to 4 substituents, including any of the substituents. L ^Two Preferred when R and A are both a single bond ^Two As the group, haloalkyl
Amino (where halo is CF _Three ), Alkylamino, cycloalkylamino, arylamino, heteroarylamino, alkoxyamino, aryloxy
Cyamino, heteroaryloxyamino, heterocyclic amino (where heterocyclic is nitrogen
Or bonding to a carbonyl group via a carbon atom). L ¹ Is a linking group containing from 1 to 10 carbons in a straight chain, including alkylene, alkenylene or alkynylene, wherein one or two alkenes in the linking chain;
Optionally substituted with one or two alkynes, oxygen, alkyl or aryl
May contain an amino group, an oxo group, and 1 to 5 alkyl or
It may be substituted with a halo group (preferably F). L ^Two Is the above L ¹ May be the same as or different from ^Two Is independently L ¹ Base
Or a single bond. R ^Three , R ^Three ', R ^Four And R ^Four 'Are the same or different and are each independently H
, Halogen, CF _Three , Haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alka
Noyl, nitro, amino, thiol, alkylthio, alkylsulfinyl,
Alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl,
Alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl,
Cycloheteroalkylalkyl, cyano, Ar-, Ar-alkyl, ArO, A
r-amino, Ar-thio, Ar-sulfinyl, A-sulfonyl, Ar-carbo
Nil, Ar-carbonyloxy or Ar-carbonylamino (where Ar-
Is aryl or heteroaryl, and Ar is optionally condensed to Ar
May contain one, two or three rings). R ^3a And R ^3b Are the same or different and are each independently ^Three Any of the groups. Embedded image Are the same or different and each independently has 1, 2, 3 or 4
5- or 6-membered heteroatoms containing terror atoms (which, independently, are N, S or O)
A loaryl ring, including its N-oxide. X (of a fluorenyl-type ring) is a bond or a compound of the formula: Embedded image Wherein Y is O, NR ⁶ Or S; n ′ is 0, 1 or 2; R ⁶ Is H, lower alkyl, aryl, -C (O) -R ¹¹ Or —C (O) —O—R ¹¹ R ⁷ And R ⁸ Are the same or different and are each independently H, alkyl,
Reel, halogen or -OR ¹² Or R ⁷ And R ⁸ May together form oxygen to form a ketone; R ⁹ , R ^Ten , R ⁹ 'And R ^Ten 'Are the same or different and are each independently
H, lower alkyl, aryl or -OR ¹¹ R ⁹ "And R ^Ten "Are the same or different and are each independently H, lower alkyl, aryl, halogen or -OR. ¹¹ R ¹¹ Is alkyl or aryl; R ¹² Is H, alkyl or aryl, provided that when A is a bond (1), R ^Two L ^Two Must not be H. Pharmaceutically acceptable salts of the compounds of the present invention of formula I include lithium, sodium
Or alkali metal salts such as potassium;
Alkaline earth metal salts; zinc or aluminum cations, and ammonium,
Phosphorus, diethanolamine, ethylenediamine, t-butylamine, t-octy
Other cations such as amines, deamines and chlorides;
Lomide, iodide, tartrate, acetate, methanesulfonate, maleate
Pharmaceutically acceptable anions such as succinate, glutarate, etc .;
Natural products such as luginine, lysine, alanine and their prodrug esters
Salts of produced amino acids may be mentioned. In addition, according to the present invention, atherosclerosis, pancreatitis, hyperglycemia or obesity
Provided is a method of preventing, suppressing or treating the above, wherein the method of formula I, IA
Or use IB compounds to reduce the activity of microsomal triglyceride transfer proteins
Administer in smaller amounts. Further, according to the present invention, serum lipid levels, cholesterol and / or
Lowers glycerides or hyperlipidemia, hyperlipidemia, hyperlipoproteinemia,
Hypercholesterolemia, atherosclerosis, hyperglycemia, pancreatitis, obesity, high bird
Inhibits and / or treats glyceridemia, type II diabetes (NIDDM)
Provided in the method, wherein the compound of formula I described above is treated with microsomes.
It is administered in an amount that reduces the activity of the glyceride transfer protein. DETAILED DESCRIPTION OF THE INVENTION The definitions set forth below are used throughout this specification unless otherwise specified.
Applied to the phrase. The phrase “MTP” means (1) when obtained from living organisms (eg, cows, humans, etc.),
And (2) triglycerides.
Cholesterol esters or phospholipids, synthetic phospholipid vesicles, membranes or
Stimulates the transport of poprotein to synthetic phospholipids, membranes or lipoproteins, and
Cholesterol transesterification protein which may have similar catalytic properties [Drayna et al. 327 632-634, 1987)]. As used herein, “stabilizing” atherosclerosis refers to a new atherosclerosis
Refers to reducing the onset of sclerosing damage and / or suppressing the formation of the damage
You. As used herein, “regress” of atherosclerosis refers to atherosclerosis.
Refers to reducing and / or eliminating chemical damage. The phrase “lower alkyl” as used herein alone or as part of another group
, "Alkyl" or "alk", unless otherwise indicated,
Linear chain having 1 to 40, preferably 1 to 20, more preferably 1 to 12 carbon atoms
And branched chain hydrocarbon groups, e.g., methyl, ethyl, propyl,
Isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl,
Xyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trime
Chillpentyl, nonyl, decyl, undecyl, dodecyl, and their various branched chains
Sex, etc., and these groups, ^Three Group or R ¹ Substituent
And those having 1 to 4 substituents which may be any of the above. The term “cycloalkyl” as used herein alone or as part of another group
Unless otherwise specified, the term “total number of rings forming a ring is 3 to 20, and
Or one aromatic ring containing 4 to 12 carbons and as described for aryl
Including monocyclic alkyl, dicyclic alkyl and tricyclic alkyl.
Saturated or partially unsaturated having 1 to 3 rings (containing 1 or 2 double bonds)
A) cyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclo
Pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and
And cyclododecyl, cyclohexenyl, And any of these, if necessary, may be selected from the group represented by R described in the present specification. ^Three Group or R ¹ It may be substituted with one to four substituents which may be any of the groups. The term “cycloalkenyl” as used herein alone or as part of another group
"" Means 5-20, preferably 6-12 carbons and one or two doubles.
Refers to a cyclic hydrocarbon group having a bond. Specific examples of the cycloalkenyl group include
, Cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl
, Cyclohexadienyl and cycloheptadienyl, which are necessary
May be substituted as described for cycloalkyl. As used herein, the phrase "polycycloalkali" as used alone or as part of another group.
"Kill" means 5-20 carbons and 0-3 bridges, preferably 6-12 carbons.
A bridged polycyclic group containing carbon and one or two bridges is designated. Polycyclo
Specific examples of the alkyl group include [3.3.0] -bicyclooctanyl, adaman
Tanyl, [2.2.1] -bicycloheptanyl, [2.2.2] -bicyclooctane
Tanyl, etc., which are described as necessary for cycloalkyl, if necessary.
May be substituted as follows. As used herein, the phrase “polycycloalkyl”, alone or as part of another group
“Kenyl” refers to 5-20 carbons, 0-3 bridges and one or two double bonds.
, Preferably a bridged polycycle containing from 6 to 12 carbons and one or two bridges
Refers to a formula group. Specific examples of the polycycloalkenyl group include [3.3.0]-
Bicyclooctenyl, [2.2.1] -bicycloheptenyl, [2.2.2]-
Bicyclooctenyl and the like.
May be substituted as described above. The phrase “aryl” as used herein alone or as part of another group is
Monocyclic and dicyclic aromatic groups containing 6 to 10 carbons in the ring portion (e.g.,
Phenyl or naphthyl), which are optionally fused to Ar
One to three rings (e.g., aryl, cycloalkyl, heteroaryl,
Cycloheteroalkyl ring), and if necessary, via an available carbon atom.
, Hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloal
Coxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl
, Cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkyl
Kill, aryl, heteroaryl, arylalkyl, aryloxy, aryl
Ruoxyalkyl, arylalkoxy, arylthio, arylazo, hetero
Arylalkyl, heteroarylalkenyl, heteroarylheteroaryl
, Heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino [
Wherein amino is one or two substituents (eg, alkyl, aryl or
Any of the other aryl compounds described in the above)), thiol, alkyl
Ruthio, arylthio, heteroarylthio, arylthioalkyl, alkoxy
Cyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminoca
Rubonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl
, Alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonyl
Ruamino, arylcarbonylamino, arylsulfinyl, arylsulf
Ynylalkyl, arylsulfonylamino or arylsulfonaminoca
Rubonyl or R as described herein ^Three Group or R ¹ Selected from any of the substituents
It may be substituted with one, two or three groups. The term “aralkyl” as used herein alone or as part of another group,
“Aryl-alkyl” or “aryl-lower alkyl” is alkyl as defined above.
A group having an aryl substituent, such as benzyl or
Phenethyl or naphthylpropyl, or aryl as described above. The phrase "lower alkoxy" as used herein alone or as part of another group.
"", "Alkoxy", "aryloxy" or "aralkoxy"
The alkyl, aralkyl or aryl group bonded to an oxygen atom is included.
You. The phrase “amino” as used herein alone or as part of another group is required
Depending on one or two substituents, for example alkyl, aryl, aryl
Kill, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cyclo
It may be substituted with roheteroalkylalkyl and / or cycloalkyl. The phrase "lower alkylthio" as used herein alone or as part of another group.
“O”, “alkylthio”, “arylthio” or “aralkylthio”
Wherein the above alkyl, aralkyl or aryl group is bonded to a sulfur atom
Is done. As used herein, the phrase “lower alkyla”, used alone or as part of another group.
“Amino”, “alkylamino”, “arylamino” or “arylalkyl
“Mino” includes the above alkyl, aryl or arylalkyl group represented by a nitrogen atom
And those bonded to are included. The term “acyl” as used herein by itself or as part of another group is referred to as
Refers to an organic group bonded to a carbonyl (C = O) group,
Examples include alkanoyl, alkenoyl, aroyl, aralcanoyl, hetero
Aroyl, cycloalkanoyl and the like can be mentioned. The phrase "alkanoyl" as used herein alone or as part of another group.
"" Means that alkyl is bonded to a carbonyl group. The phrase “lower alkyl” as used herein by itself or as part of another group
“Nyl” or “alkenyl” refers to a normal chain carbon, unless otherwise indicated.
A prime number of 2 to 20, preferably 3 to 12, more preferably 2 to 8, and 1
A straight or branched group having from 6 to 6 double bonds, for example vinyl, 2-
Propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl,
2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-hept
Thenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4
-Dodecenyl, 4,8,12-tetradecatrienyl and the like.
Optionally, 1-4 substituents, i.e., halogen, haloalkyl, alkyl,
Alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloa
Alkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alka
Noylamino, alkylamide, arylcarbonylamino, nitro, cyano,
Thiol, alkylthio or R as described herein ^Three Group or R ¹ Any of the substituents
May be replaced by The term “lower alkyl” as used herein by itself or as part of another group
“Nyl” or “alkynyl” means normal chain charcoal unless otherwise specified.
A prime number of 2 to 20, preferably 2 to 12, more preferably 2 to 8;
Refers to a straight or branched chain group having three triple bonds, for example, 2-propynyl,
3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl
, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-
Octynyl, 3-noninyl, 4-decynyl, 3-undecynyl, 4-dodecynyl
And the like, if necessary, from 1 to 4 substituents, that is, halogen,
Haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, a
Reel alkyl, cycloalkyl, amino, heteroaryl, cycloheteroaryl
Kill, hydroxy, alkanoylamino, alkylamide, arylcarbonyl
Amino, nitro, cyano, thiol, and / or alkylthio, or
R in the detailed description ^Three Group or R ¹ It may be substituted with any of the substituents. The term “alkylene,” as used herein alone or as part of another group, refers to 2
The above alkyl group having a single bond for bonding to another group at two different carbon atoms
And may be optionally substituted as described for “alkyl”. The term “alkenylene” as used herein alone or as part of another group
And "alkynylene" are each a single bond for bonding at two different carbon atoms.
The above-mentioned alkenyl group and alkynyl group having a bond are referred to. Suitable alkylene, alkenylene or alkynylene groups described herein
Or (CH _Two ) M, (CH _Two ) N or (CH _Two ) P, which may include an alkylene, alkenylene or alkynylene group, are optionally described herein.
R ^Three Group or R ¹ Having 1, 2 or 3 substituents, including any of the substituents
May be. Specific examples of alkylene, alkenylene and alkynylene include: Embedded image Is mentioned. The terms “halogen” or “ha” as used herein alone or as part of another group.
"B" means chlorine, bromine, fluorine and iodine, and CF _Three And chlorine or fluorine is preferred. The phrase “metal ion” refers to an alkali such as sodium, potassium or lithium.
Li metal ions and alkaline earth metal ions such as magnesium and calcium
, And zinc and aluminum. As used herein, the term "heterocycle" refers to a "cycloheteroalkyl" as described herein.
The term "cycloheteroalkyl" group is used herein, alone or as part of another group.
"Has 1 to 2 heteroatoms (e.g. nitrogen, oxygen and / or sulfur).
And if possible via a carbon or heteroatom a linking group (CH _Two ) Designates a 5-, 6- or 7-membered saturated or partially unsaturated ring linked via p (described above)
For example, And the like. These groups have 1 to 4 substituents, such as alkyl, halo,
Oxo and / or R as described herein ^Three Group or R ¹ Having any of the substituents
May be. In addition, any of the above rings may be cycloalkyl, aryl, heteroaryl
Or a cycloheteroalkyl ring. The term “cycloheteroalkoxy” as used herein alone or as part of another group
"" Means at least one oxygen atom and at least one or two other
Having terror atoms (eg, nitrogen, oxygen and / or sulfur),
Via an atom, if possible, a linking group (CH _Two ) Refers to a 4, 5, 6 or 7 membered saturated or partially unsaturated ring linked via p, for example And the like. These groups have 1 to 4 substituents, such as alkyl, halo,
Oxo and / or R as described herein ^Three Group or R ¹ Having any of the substituents
May be. In addition, any of the above rings may be cycloalkyl, aryl, heteroaryl
Or a cycloheteroalkyl ring. The term “heteroaryl,” as used herein alone or as part of another group, is
With 1, 2, 3, or 4 heteroatoms (eg nitrogen, oxygen or sulfur)
5- or 6-membered aromatic ring, and aryl, cycloalkyl, heteroaryl of the ring
Or cycloheteroalkyl rings (eg benzothiophenyl, indolyl
)), And includes its N-oxide. And the like. Ar may be any of the above aryl or heteroaryl. Embedded image Are the same or different as described above, and are adjacent positions (ie, ortho or 1
, 2) to the central ring of the indenyl or fluorenyl type group. Of such groups
As a specific example, Where u is O, S and NR ^7a Selected from R ^7a Is H, lower al
Kill, aryl, -C (O) R ^7b , -C (O) OR ^7b R ^7b Is alkyl or
It is a reel. The heteroaryl group containing the above groups may optionally have 1 to 4 substituents, for example
R described in this specification ^Three Group or R ¹ It may have any of the substituents. In addition, heels
All rings are cycloalkyl, aryl, heteroaryl or cyclohetero.
It can be fused to a loalkyl ring. The phrase "cycloheteroalkyl," as used herein alone or as part of another group.
“Alkyl” means that the above-mentioned cycloheteroalkyl group is linked via a C atom or a heteroatom.
(CH _Two ) Refers to those linked to the p-chain. The phrase "heteroarylalkyl," as used herein alone or as part of another group.
Or "heteroaryl-alkenyl" means that the above heteroaryl group is C
And the above-mentioned — (CH _Two ) P-chain, alkylene or alkenylene. As used herein, the phrase "polyhaloalkyl" refers to two to nine, preferably two to nine.
The above “A” having five halo substituents (eg, F or Cl, preferably F)
"Kirkyl" group, for example CF _Three CH _Two , CF _Three Or CF _Three CF _Two CH _Two Is raised
Can be In the compound of formula I, A is NH; B is X is a bond, oxygen or sulfur; R ^Three And R ^Four Is independently H or F
Is preferred. Preferred R ^Two The group can be an alkyl, polyfluoroalkyl (eg, 1,1,1-trifluoroethyl), alkenyl, aryl, heteroaryl, or heteroaryl.
Reelalkyl, such as 2-pyridylmethyl (preferably the preferred R ^Two Substituted with one of the substituents). L ¹ Contains 2 to 7 atoms in a straight chain; ^Two Is a bond or lower alkylene
Is preferred. Preferred L ^Two The group is CH _Two Or an alkylene or bond. A preferred A group is -NH-. Preferred R ¹ The groups are those described in the preferred compounds of the formula below. In the compound of the present invention, R ¹ Those having a structure in which CO, n and arrangement are shown below are more preferable. Embedded image Compounds of formula I may be prepared by the specific methods described in the schemes shown below.
. Specific reagents and procedures for these reactions are described below and in the Examples below.
It is as follows. The method for producing a starting material used for producing the cyclophosphonate according to the present invention is described below.
Shown by the reaction formula. Reaction formula 1 Embedded image As is clear from the above reaction formula 1A, the serinol derivative (2) was converted to a carbodiimide
-The compound (3) can be directly obtained by acylation by coupling. Alternative
Then, as shown in the reaction formula 1B, the compound (2) is acylated with an acid chloride.
The triacylate compound (4) is obtained and then subjected to solvolysis to give the diol (3)
Can be obtained. Also, as shown in Reaction Formula 1C, diol (3)
Acylation from an S-O-trimethylsilylated amine (5) with an acid chloride,
Alternatively, it can be produced by methanolysis. In subsequent reactions, unless otherwise indicated, starting materials, intermediates, and
Component "B" of the final product is, for illustrative purposes only, It will be appreciated that it is described as In all reactions described herein, starting materials, intermediates and end products
The component “B” is Any of the fluorenyl-type groups of Will be understood to be any of the indenyl type groups of The above component B (including all fluorenyl-type groups and all indenyl-type groups)
, Collectively referred to as "fluorenyl-type" components. The first fluoreni in the reaction equation
The use of carboxylic groups (described in the preceding paragraph) is for illustration purposes only;
In any of the above reaction formulas, Instead of any of the above three fluorenyl or four indenyl groups
May also be used. The compounds of Formula I of the present invention can be prepared as shown in Scheme 2 below. Reaction formula 2 Embedded image As apparent from the above reaction scheme 2, dialkyl phosphonate ester (Im)
With bromotrimethylsilane, followed by oxalyl chloride and dimethylformyl.
Treatment with muamide (using normal procedures) to afford the diphosphinyl dichloride intermediate
To obtain the diol (3) (which may be chiral or achiral) without purification.
(Formed with Schemes 1A, 1B or IC) and an amine base (eg, triethyl
With the 7-trans and 7-cis isomers of the invention (each
, Io and Ip). The 7-trans and 7-cis isomers are commonly
It can be separated by conventional chromatographic methods. [0057] Reaction formula 3 Preparation of Other Acyl Derivatives from 7-Trans Compound ¹ 'Is arylmethyloxy or heteroarylmethyloxy. Embedded image As is apparent from the above Reaction Scheme 3, the 7-trans isomer (Io ′) (R ¹ '= O CH _Two C ₆ H _Five ) (And the corresponding 7-cis isomer) are subjected to hydrogenolysis to form an amine intermediate, which is ¹ CO _Two H to react with another acyl derivative according to the present invention.
Can be manufactured. The starting material (Im) can be prepared according to the following Reaction Schemes 4 and 4A
You. Reaction formula 4 Embedded image In the formula, Hal is translated as halo, and so on. PG is an oxygen protecting group such as t-Bu
(CH _Three ) _Two Si- or t-Bu (Ph) _Two Si-. Embedded image Where Q ¹ Is alkyl, triorganosilyl (eg, trimethylsilyl or t-butyldimethylsilyl), H, the latter being butyllithium, sodium hydride
In the presence of a base such as sodium or bis- (trimethylsilylamide)
Is the case. [0059] Reaction formula 4A (Alternative method for producing compound Ih) The protected alcohol XIVa can be converted to a variety of compounds via the intermediate halide (Ih).
It can be translated into functional groups across. For example, alcohol Ig can be sulfo
Nate esters (tosyl chloride or mesyl chloride) and iodine substitution (acetone or
Or activation with NaI or KI in 2-butanone, or
Sphin, I _Two And by reaction with imidazole, it can be converted to the halide (Ih) of the present invention. The halide (Ih) is subjected to the Arbuzov reaction,
Form phosphonates, phosphinates and phosphine oxides (Im)
Can be. The Arbuzov reaction involves phosphite, phosphinite and phosphonite.
G [for example, (alkyl O) _Three P or (alkyl O) _Two POSi (alkyl) _Three Or (alkyl O) _Two POH, the latter in the presence of a base such as butyllithium, sodium hydride or sodium bis (trimethylsilylamide)
] At a temperature in the range of about −20 to + 180 ° C. The starting material VIIIA for compound (Im) is as shown in Scheme 5 below
And can be manufactured. Reaction formula 5 (Amide) A is Preparation of a compound of formula I which is As is evident in Scheme 5, amide VIIIA can be used to convert compound II to dichlorometh
In an inert organic solvent such as dimethylformamide (DMF)
In the presence), treated with thionyl chloride or oxalyl chloride to give the formula: By forming the acid chloride IIA. That is, acid chloride
The IIA is separated from the reaction mixture at a low temperature in the range of about -40 ° C to room temperature,
Min (R ^Two L ^Two ) R ^Five Treatment with NH forms the amide VIIIA. The amide VIIIA was converted to the compound of formula I using the procedure described in Scheme 4 / 4A.
Can be interchanged. In performing the above reaction, an optional tertiary amide VIIIA is formed.
Of amine and acid chloride IIA in the presence of a secondary amine base or other oxygen scavenger
The ratio is set within the range of about 4: 1 to 1: 1. Acids II and (R ^Two L ^Two ) R ^Five An alternative method for amide VIIIA formation from NH can be performed by general literature procedures. Reaction formula 6 (Ester) Preparation of Ester VIIIA (A = —O—) As evident in Reaction Scheme 6, the ester compound of Formula VIIIB where A = oxygen
H in the presence of an alcohol such as lyl alcohol, ethanol or methanol _Two SO _Four Alternatively, it can be produced by acid-catalyzed esterification of acid II using an acid such as p-toluenesulfonic acid. Alternatively, activation of acid II to acid chloride
(Using oxalyl chloride or thionyl chloride) and then, if necessary, a tertiary amine.
Treatment with an alcohol in the presence of a base or other oxygen scavenger to produce a compound of formula VI
The compound of IIB is obtained. Various other methods of activation include mixed anhydride formation [(CF _Three COO) _Two Or
i-BuOCOCl] or acylimidazole (carbonyldiimidazole)
Or DCC and H in the presence of DMAP (4-dimethylaminopyridine)
Use of OBT. These activated intermediates are treated with alcohol.
Then, an ester is easily formed. Reaction formula 7 (Amide from isocyanate) Production of amide VIIIC (A is NH) A compound of formula VIIIC (amide) wherein A is —NH— is a compound of formula IV
Can be produced by the method shown in Reaction Scheme 7. Compound IV is a base
For example, treating with n-BuLi, reacting an anion with isocyanate,
VIIIC is obtained. [0065] Reaction formula 8 Compound Im _Two Other reaction formulas for Compound Im can be modified by various transformations as described in Scheme 8. The compounds of the present invention can be administered by reducing the activity of MTP by administering a therapeutically effective amount.
Can be used to prevent, stabilize, or reverse atherosclerosis in mammals.
Can be used. For compounds of the present invention, MTP isolated from one of the following sources was used and S.
Patent application no. 117362 (filed on Sep. 3, 1993)
, MTP inhibitory activity can be tested. (1) bovine liver microsomes, (2) HepG2 cells (human hepatoma cells), or (3) recombinant human MTP expressed in baculovirus. The compounds of the present invention may be administered in a therapeutically effective amount to reduce the activity of MTP.
Depending on the serum lipid level of the mammal, such as cholesterol or triglyceride.
It can also be used to lower TG levels. The compound of the present invention can be used for various other symptoms or substances using an agent that reduces the activity of MTP.
Can be used to treat disease. For example, the compounds of the present invention can reduce the amount or activity of MTP.
Reduces serum cholesterol and TG levels, and thus TG, fatty acids
And reduce cholesterol absorption, resulting in hypercholesterolemia,
Liglyceridemia, hyperlipidemia, hyperlipoproteinemia, hyperlipidemia, pancreatitis, hypertension
Glycemia, atherosclerosis, non-insulin dependent diabetes (type II diabetes) and
And for the treatment of obesity. The compounds of the present invention are agents that reduce the activity of MTP,
It is administered to various mammals in need, such as monkeys, dogs, cats, rats, and humans.
Can be These agents may be administered systemically, for example, orally or parenterally.
Can be given. The agent that reduces the activity or amount of MTP may be a conventional systemic dosage form,
For example, they can be prepared as tablets, capsules, elixirs or injections.
. Such dosage forms also include the necessary physiologically acceptable carrier materials, excipients, and lubricants.
, Buffers, antibacterial agents, bulking agents (eg mannitol), antioxidants (ascorbin)
Acid or sodium bisulfite). Oral dosage forms are preferred, but
The oral dosage form also gives satisfactory results. The dosage depends on the age, weight, and condition of the patient, as well as the route of administration, dosage form, and lifestyle.
Care must be taken according to the rules and the desired result. In general,
In the above dosage forms, about 5 to 50 in one or two to four divided doses per day.
It may be administered in an amount of 0 mg / day. BEST MODE FOR CARRYING OUT THE INVENTION The following examples are preferred specific examples of the present invention. All temperatures are unique
All units are in ° C unless otherwise indicated. Note: The phrase “flash chromatography” is a trademark of EM Industries
Silica Gel 60 (Catalog # 9385-9) (23 under 10-20 psi nitrogen pressure)
(0-400 mesh). Example 1 (E) -9- [4- [2-oxo-5-[[[4 ′-(trifluoromethyl)
[1,1′-biphenyl] -2-yl] carbonyl] amino] -1,3,2-di
Oxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoroe
(Tyl) -9H-fluorene-9-carboxamide.N-oxide Example 2 (Z) -9- [4- [2-oxo-5-[[[4 ′-(trifluoromethyl)
-[1,1′-biphenyl] -2-yl] carbonyl] amino] -1,3,2-
Dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoro
Ethyl) -9H-fluorene-9-carboxamide.N-oxide A. Embedded image 1.33 g (5.00 mmol) of 4'-triol in 10 ml of dichloromethane
Fluorophenyl-2-benzoic acid (Aldrich Chemical Co.), 0.4
55 g (5.00 mmol) of serinol (Aldrich Chemical Co.)
, 0.750 g (5.0 mmol) of HOBt and 0.5 ml (3.6 mmol)
L) in a stirred solution of triethylamine at room temperature under argon at room temperature.
Mmol) of EDCI is added in small portions over 3 minutes. After 16 hours (h),
The reaction mixture is diluted with ethyl acetate, once with saturated sodium bicarbonate solution and once with brine.
Wash once with 10% citric acid solution and dry (MgSO 4) _Four ) And evaporate. Purify by flash chromatography on silica gel (5 × 15 cm column, ethyl acetate)
To give the title compound as a white solid. mp 146-148 ° C, 1.23g (
Yield 72%). B. Embedded image B (1). Embedded image 9-Fluorenecarboxylic acid (Aldrich) in THF (1200 ml) (5
0 g, 240 mmol) in a solution of n-butyllithium / THF at 0 ° C.
2.5M, 211 ml, 530 mmol) are added dropwise. Yellow reaction solution at 0 ° C for 1 h
And then add 1,4-dibromobutane (31.3 ml, 260 mmol) in 3 portions.
Add dropwise over 0 minutes. The reaction was stirred at 0 ° C. for 30 minutes, then the reaction was
h Warm up to room temperature (RT). The reaction solution is extracted with water (750 ml × 3). Con
The combined aqueous layers are extracted with ethyl ether (800 ml). HCl aqueous layer
Acidify with a solution (1N, 500 ml) and then dichloromethane (750 ml × 3)
) To extract. The combined organic layer was washed with MgSO _Four Dry on top. Evaporation gives the title compound (71 g, 85%) as a white solid. B (2). Embedded image CH _Two Cl _Two B (1) acid (60 g, 173 mmol) and
Oxalyl chloride (CH 2) was added to a solution of _Two Cl _Two 2.0 M, 104 ml, 208 mmol) are added dropwise. Reaction solution at 0 ° C
Stir for 10 minutes, then warm to RT and stir for 1.5 h. The reaction solution was concentrated under reduced pressure.
To give the crude acid chloride as a yellow oil. CH _Two Cl _Two 2,2 in (500ml)
Suspension of 2-trifluoroethylamine hydrochloride (25.9 g, 191 mmol)
To the solution was added triethylamine (73 ml, 521 mmol) at 0 ° C. under argon.
After that, the crude acid chloride / CH _Two CH _Two (15 ml) of the solution are added dropwise. Reaction solution at 0 ° C
And stir for 1 h _Two Cl _Two (500 ml), water (300 ml x 2), 1
N-HCl (300 ml × 2), saturated NaHCO _Three (300 ml × 2) and brine (300 ml × 2), then MgSO _Four Dry on top. Evaporation gave 80 g of an oil which was flash chromatographed on silica gel (2.5 kg).
Purify by chromatography. The crude product is CH _Two Cl _Two / Hexane mixture and 10
% EtOAc / Hexane (4 L) to 15% EtOAc / Hexane (2 L) to 20
Elute with a step gradient of 4% EtOAc / hexane (4 L). Combine pure fractions
And evaporated to give the title compound (52.5 g, 71%) as a white solid (mp8
8-92 ° C). B (3). Embedded image The above B (2) compound (2.13 g, 3.53 ml of triethyl phosphite)
5.00 mmol) was heated to 110 ° C. under argon for 16 h, then 18
Heat to 0 ° C. for 4 h. Cool the reaction and then evaporate volatiles at 100 ° C and 1 torr
I do. The residue was flash chromatographed (5 × 15 cm column, EtOAc
) To give the title compound (1.92 g, 79%) as a waxy yellow solid
(Mp 87-89 ° C). MS (FAB) m / e484 (M + H) Elemental analysis (C _{twenty four} H ₂₉ NO _Four PF _Three +0.13 mol H _Two (Calculated as O) Calculated values: C59.33, H6.07, N2.88, P6.37, F11.73 Measured values: C59.09, H5.98, N2.95, P6.51, F11.92 C. (E) -9- [4- [2-oxo-5-[[[4 ′-(trifluoromethyl
L) [1,1′-biphenyl] -2-yl] carbonyl] amino] -1,3,2
-Dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoro
(Roethyl) -9H-fluorene-9-carboxamide.N-oxide (Example 1
D. (Z) -9- [4- [2-oxo-5-[[[4 ′-(trifluoromethyl
L)-[1,1'-biphenyl] -2-yl] carbonyl] amino] -1,3,
2-dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoro
(Oroethyl) -9H-fluorene-9-carboxamide N-oxide (Example
2) 500 mg (1.03 mmol) of the above B compound in 10 ml of dichloromethane
0.45 ml (3.4 mmol) of bromo was added to the stirred solution of the product at room temperature under argon.
Add trimethylsilane. After 1 h, the reaction mixture was evaporated to a thick oil
Get things. The oil was dissolved in 5 ml of dichloromethane at room temperature under argon,
Treatment with 26 ml (3.0 mmol) oxalyl chloride and 100 μl DMF
I do. After 2 h, the reaction mixture is evaporated and redissolved in 10 ml of dichloromethane.
340 mg (1.0 mmol) of the above compound A was added to this solution at room temperature under argon.
And 0.5 ml (3.6 mmol) of triethylamine are added. 14 hours later,
The reaction was diluted with ethyl acetate, washed once with 10% citric acid solution and dried (MgSO _Four ) And evaporate. Flash chromatography on silica gel (5 × 15 cm column, ethyl acetate / hexane (85:15, 1 L), then ethyl acetate)
To obtain two fractions. The less polar fraction is the above-mentioned C compound (Example 1). White solid, mp 105-
107 ° C., 205 mg, 27% yield. Microanalysis (C ₃₇ H ₃₃ F ₆ N _Two O _Five P + 0.55H _Two Calculated: C60.01, H4.64, N3.78, F15.39, P4.18 Observed: C60.00, H4.48, N3.64, F15.10, P3.75 MS (electro Spray, + ion) m / e731 The fraction with high polarity is the D compound (Example 2). White solid, mp102
１０４104 ° C., 130 mg, 17%. ¹ H-NMR, ¹³ C-NMR, IR and mass spectrometry measurements were consistent with the index compound. Microanalysis (C ₃₇ H ₃₃ F ₆ N _Two O _Five P + 0.64H _Two Calculated: C59.88, H4.66, N3.77, F15.36, P4.17 Actual: C59.88, H4.44, N3.75, F15.08, P4.14 MS (electro Example 3 trans-9- [4- [5- (benzoylamino) -2-oxo-1,3,2
-Dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoro
(Roethyl) -9H-fluorene-9-carboxamide A. N- (1,3-dibenzoxyloxy-2-propyl) benzamide 1.82 g (20.0 mmol) of serinol in 20 ml of dichloromethane
And a stirred slurry of 9.2 ml (66 mmol) of triethylamine.
At −5 ° C., 7.0 ml (61 mmol) of benzoyl chloride (Aldrich)
) Is added dropwise over 30 minutes. After 2 h, the reaction was diluted with ethyl acetate and
Wash three times with acid, once with brine, twice with saturated sodium bicarbonate solution and dried (MgSO _Four ) And evaporate. The obtained white solid is recrystallized from ethyl acetate / hexane to give the title compound (mp 96-98 ° C, 5.62 g, yield 70%). B. N- (1,3-dihydroxy-2-propyl) benzamide 160 mg (4.0 mmol) of 60% sodium hydride in 50 ml of methanol
4.03 g (10.0 mmol) on a stirred solution of lithium at room temperature under argon
Add compound A as described above. Heating the slurry to reflux forms a clear solution. 3 hours later
Cool the reaction and add 1.5 ml of 4N hydrogen chloride / dioxane. Evaporation and
And methanol to re-evaporate to silica gel (5 g), followed by silica gel (5 × 15
cm, column / methanol / ethyl acetate = 3:47)
The title compound was obtained as a white solid (1.22 g, yield 62).
%). C. Trans-9- [4- [5- (benzoylamino) -2-oxo-1,3
, 2-Dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trif
(Fluoroethyl) -9H-fluorene-9-carboxamide 699 mg (1.45 mmol) of Example 1 / B in 5 ml of dichloromethane.
0.63 ml (4.8 mmol) of butyl was added to the stirred solution of the compound at room temperature under argon.
Add lomotrimethylsilane. After 1 h, the reaction mixture was evaporated to a thick
Obtain an oil. The oil was dissolved in 3 ml of dichloromethane at room temperature under argon,
Treated with 0.26 ml (3.0 mmol) oxalyl chloride and 50 μl DMF
Manage. After 2 h, the reaction mixture is evaporated and redissolved in 3 ml of dichloromethane.
To this solution was added 283 mg (1.45 mmol) of Example 3 / at room temperature under argon.
Compound B and 0.6 ml (4.3 mmol) of triethylamine are added. 2
After h, the reaction was diluted with ethyl acetate, washed once with 10% citric acid solution and dried (M
gSO _Four ) And evaporate. Purification by flash chromatography on silica gel (5 × 15 cm column, ethyl acetate) gives the title compound as a white solid (m
166-168 ° C, 245 mg, 29% yield). Microanalysis (C ₃₀ H ₃₀ F _Three N _Two O _Five P + 0.5H _Two (As O) Calculated: C 60.50, H 5.25, N 4.70, F 9.57 Found: C 60.47, H 5.01, N 4.62, F 9.30 MS (electrospray, + ion) m / e 587 Example 4 Trans-9- [5- [2-oxo-5-[[[4 ′-(trifluoromethyl
)-[1,1′-Biphenyl] -2-yl] carbonyl] amino] -1,3,2
-Dioxaphospholinan-2-yl] pentyl] -N- (2,2,2-trifur
(Oroethyl) -9H-fluorene-9-carboxamide Example 5 cis-9- [5- [2-oxo-5-[[[4 ′-(trifluoromethyl)-
[1,1′-biphenyl] -2-yl] carbonyl] amino] -1,3,2-di
Oxaphospholinan-2-yl] pentyl] -N- (2,2,2-trifluoro
Ethyl) -9H-fluorene-9-carboxamide A. 2-amino-1,3-bis (trimethylsilyloxy) propane 4.25 ml (20.1 mmol) containing one drop of bromotrimethylsilane
Stirring 1.84 g (20.0 mmol) of serinol in xamethyldisilazane
The solution is heated to 180 ° C. under argon. After 16 h, the reaction mixture was partially cooled
Distilled at 0.6 torr and the fractions at bp 44-47 ° C were collected to give the title compound as a colorless liquid.
Obtained in body (4.05 g, 86%). B. N-[(1,3-dihydroxy) -2-propyl] -2- (4-trifur
(Oromethylphenyl) benzamide 3.88 g (16.5 mmol) of the above compound A in 20 ml of THF and
At 0 ° C., a solution of 2.40 ml (17.2 mmol) of triethylamine at 10 ° C.
4'-trifluoromethyl-2-biphenylcarbonyl chloride in ml of THF
A solution of the compound [prepared from 4.40 g (16.5 mmol) of the corresponding carboxylic acid]
Add dropwise over 10 minutes. The resulting slurry was stirred for 1 h, diluted with ether
, Filter and evaporate the filtrate. Dissolve the residual oil in 50 ml of methanol and add
Treat with 5 ml of 4M hydrogen chloride / dioxane. After stirring at room temperature for 1 hour, the reaction solution was steamed.
Evolved and the white solid was recrystallized from ethyl acetate / hexane to give the title compound (m
p146-148 ° C, 5.08 g, 91% yield). C. Embedded image C (1). Embedded image 9-Fluorenecarboxylic acid (Aldrich) (10 ml) in THF (250 ml)
g, 48 mmol) at 0 ° C. in a solution of n-butyllithium / THF (2
. 5M, 42.2 ml, 106 mmol) are added dropwise. Yellow reaction solution at 0 ° C for 1 h
And then add 1,5-dibromobutane (16.8 ml, 124 mmol) in 3 portions.
Add dropwise over 0 minutes. The reaction was stirred at 0 ° C. for 30 minutes, then the reaction was allowed to reach RT
For 30 h. The reaction solution is extracted with water (150 ml × 3). Combined
Extract the aqueous layer with ethyl ether (160 ml). The aqueous layer was washed with HCl solution (1N
, 100 ml) and then extracted with dichloromethane (150 ml × 3).
You. The combined organic layer was washed with MgSO _Four Dry on top. Evaporation gives the title compound as a white solid. C (2). Embedded image CH _Two Cl _Two C (1) acid (total) and DMF (20 μl)
l) The solution of oxalyl chloride (CH _Two Cl _Two Medium 2.0M, 2
4 ml, 48 mmol) are added dropwise. The reaction was stirred at 0 ° C. for 10 minutes, then
Heat to T and stir for 1.5 h. The reaction mixture was concentrated under reduced pressure to remove the crude acid chloride into a yellow oil.
Obtain in the form. CH _Two Cl _Two (125 ml) in 2,2,2-trifluoroethyl alcohol
To a suspension of min hydrochloride (6.51 g, 48 mmol) was added tritium at 0 ° C. under argon.
After addition of ethylamine (16 ml, 115 mmol) the crude acid chloride / CH _Two Cl _Two (15 ml) of the solution are added dropwise. The reaction was stirred at 0 ° C. for 1 h, CH _Two Cl _Two (120 ml), water (100 ml × 2), 1N HCl (100 ml ×
2), saturated NaHCO _Three (100 ml × 2) and brine (100 ml × 2), then MgSO _Four Dry on top. Evaporation gives 17.6 g of an oil, which is purified by flash chromatography on silica gel (500 g).
The crude product is CH _Two Cl _Two / Hexane mixture and 10% EtOAc / hexane
(4 L) to 15% EtOAc / hexane (2 L) to 20% EtOAc / hexane
Elute with a (4 L) step gradient. Combine pure fractions and evaporate to label
The compound (14.7 g, 72%) is obtained as a white solid (mp 92-96 ° C.). C (3). Embedded image 2.69 g (6.11) in 15 ml of freshly distilled triethyl phosphite
(Mmol) of the above compound C (2) was heated at 180 ° C. under argon for 16 h.
I do. The reaction is cooled and the volatiles are distilled off at 100 ° C. and 1 torr. The residue
Triturate to ether to give the title compound (2.25 g, 74%) as a white solid
(Mp 141-143 ° C.). D. Trans-9- [5- [2-oxo-5-[[[4 '-(trifluoro
Tyl)-[1,1′-biphenyl] -2-yl] carbonyl] amino] -1,3
, 2-Dioxaphospholinan-2-yl] pentyl] -N- (2,2,2-tri
E. Fluoroethyl) -9H-fluorene-9-carboxamide (Example 4) Cis-9- [5- [2-oxo-5-[[[4 ′-(trifluoromethyl
)-[1,1′-Biphenyl] -2-yl] carbonyl] amino] -1,3,2
-Dioxaphospholinan-2-yl] pentyl] -N- (2,2,2-trifur
(Oroethyl) -9H-fluorene-9-carboxamide (Example 5) 1.68 g (3.42 mmol) of the above C compound in 10 ml of dichloromethane
1.35 ml (10.0 mmol) of broth was added to a stirred solution of the product at room temperature under argon.
Add motrimethylsilane. After 14 h, the reaction mixture was evaporated to a thick
Obtain an oil. The oil was dissolved in 10 ml of dichloromethane at room temperature under argon.
0.91 ml (10.5 mmol) oxalyl chloride and 50 μl DMF
To process. After 2 h, evaporate the reaction mixture and redissolve in 10 ml of dichloromethane
I do. To this solution was added 1.09 g (3.2 mmol) of the above B at room temperature under argon.
The compound and 1.0 ml (7.0 mmol) of triethylamine are added. 1h
Thereafter, the reaction solution was diluted with ethyl acetate, washed once with a 10% citric acid solution, and dried (Mg
SO _Four ) And evaporate. Silica gel (5 × 20 cm column, ethyl acetate / hexane (85:15, 2 L), then methanol / ethyl acetate (3:97, 2 L)
And purify by flash chromatography to obtain two fractions. The less polar fraction is the above-mentioned D compound (Example 4). White solid, mp165-
167 ° C, 805 mg, 34% yield. Microanalysis (C ₃₈ H ₃₅ F ₆ N _Two O _Five P + 0.38H _Two Calculated: C60.73, H4.80, N3.73, F15.17, P4.12 Observed: C60.73, H4.70, N3.60, F15.33, P3.88 MS (electro Spray, + ion) m / e 745 The highly polar fraction is the E compound (Example 5). White foam, mp11
0-114 ° C, 650 mg, 27%. Microanalysis (C ₃₈ H ₃₅ F ₆ N _Two O _Five P + 0.38H _Two (As O) Calculated: C60.73, H4.80, N3.73, P4.12 Observed: C60.74, H4.78, N3.55, P3.84 MS (electrospray, + ion) m / e 745. Example 6 trans- [2-oxo-2- [4- [9-[[(2,2,2-trifluoro
Ethyl) amino] carbonyl] -9H-fluoren-9-yl] butyl] -1,
3,2-Dioxaphospholinan-5-yl] carbamic acid phenylmethyl ester
Le A. N-benzyloxycarbonyl-1,3-dihydroxy-2-aminopro
Bread [100] 1.00 g (4.24 mmol) of Example 5 / A compound in 10 ml of THF
And a stirred slurry of 0.65 ml (4.7 mmol) of triethylamine.
0.6 g (4.2 mmol) of benzyloxycarbonyl at 0 ° C. under Lugon
Chloride (Aldrich) is added dropwise over 10 minutes. Warm the reaction to room temperature
And stir for 14 h. The reaction mixture is diluted with ether and filtered. Evaporate the filtrate,
The residue was dissolved in 25 ml of methanol and 2 drops of 4N hydrogen chloride / dioxane were added.
And heat the solution to 40 ° for 30 minutes. Evaporation and with hexane / ether
Triturate to give the title compound as a white solid (mp 104-106 ° C,
880 mg, 92% yield). MS (electrospray, + ion) m / z 226 Trans- [2-oxo-2- [4- [9-[[(2,2,2-trifur
Oroethyl) amino] carbonyl] -9H-fluoren-9-yl] butyl]-
1,3,2-dioxaphospholinan-5-yl] phenylmethylcarbamate
1.76 g (3.64 mmol) of Example 1 / B in 5 ml of dichloromethane
To a stirred solution of the compound at room temperature under argon was added 1.65 ml (12.6 mmol) of
Add bromotrimethylsilane. After 1 h, the reaction mixture is evaporated
Oil is obtained. Dissolve the oil in 20 ml of dichloromethane at room temperature under argon
And 1.2 ml (13.8 mmol) of oxalyl chloride and 100 μl of DM
Process with F. After 2 h, evaporate the reaction mixture and redissolve in 5 ml of dichloromethane
I do. To this solution at room temperature under argon, 820 mg (3.64 mmol) of the above
Compound A and 1.1 ml (7.9 mmol) of triethylamine are added. 2
After h, the reaction was diluted with ethyl acetate, washed once with 10% citric acid solution and dried (M
gSO _Four ) And evaporate. Purification by flash chromatography on silica gel (5 × 25 cm column, ethyl acetate / hexane = 85: 15) gave the title compound
Is obtained as a white solid (mp 160-163 ° C, 535 mg, 23% yield). MS (electrospray, + ion) m / e 617 Example 7 trans-1- (phenylmethyl) -N- [2- [4- [9-[[(2,2,
2-trifluoroethyl) amino] carbonyl] -9H-fluoren-9-yl
] Butyl] -1,3,2-dioxaphospholinan-5-yl] -2-piperidine
Carboxamide hydrochloride A. N-benzylpipecolic acid hydrochloride Ethyl pipecolic acid hydrochloride (10 g, 52 mmol) in DMF (80 ml)
), Benzyl bromide (7 ml, 57 mmol) and potassium carbonate (15 g,
(114 mmol) is stirred overnight at room temperature. The solvent is removed under reduced pressure. Residue
Is partitioned between dichloromethane (100 ml) and water (50 ml). Jig aqueous layer
Extract with dichloromethane (100 ml x 2) _Two SO _Four Dried on, then evaporated
To give a yellow oil. The crude product is treated with 8-15% ethyl acetate / hexane
Chromatography (500 g of silica gel) eluting with a gradient. Pure fractionation
Combine to give the title compound (12.3 g, 96%) as a colorless oil. B. Trans-1- (phenylmethyl) -N- [2- [4- [9-[[(2,
2,2-trifluoroethyl) amino] carbonyl] -9H-fluorene-9-
Yl] butyl] -1,3,2-dioxaphospholinan-5-yl] -2-piperi
Zincarboxamide hydrochloride 511 mg (0.829 mmol) of Example 6 in 5 ml of ethanol
And 100 mg of 10% palladium / activated carbon slurry purged with argon
At room temperature is partially evacuated and subjected to hydrogenation from a full balloon. After 16h, reaction
The mixture is purged with argon and filtered through a 0.45μ nylon filter. Steam
Evaporation followed by re-evaporation from dichloromethane gives a white foam. This substance
Is dissolved in 10 ml of dichloromethane and stirred at room temperature under argon while 2
12 mg (0.83 mmol) of the compound A (HCl salt), 125 mg (0.
83 mmol) HOBt, 175 mg (0.92 mmol) EDCI and
175 μl (1.26 mmol) of triethylamine are added. 6 hours later,
The reaction was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate.
You. Combine the organic extracts and dry (MgSO 4) _Four ) And evaporate. Purified by flash chromatography on silica gel (5 × 20 cm column, ethyl acetate)
To give the free base of the title compound. Dissolve this material in dichloromethane and add
. Treat with 3 ml of 4M hydrogen chloride / dioxa and evaporate to give the title compound as a white solid
(Mp 125-128 DEG C., 365 mg, 61% yield). Microanalysis (C ₃₆ H ₄₁ F _Three N _Three O _Five P + HCl + 1 dioxane + 0.33H _Two O
Calculated values: C59.01, H6.27, N5.16, Cl4.35, F7.00 Actual values: C59.00, H6.25, N5.11, Cl4.14, F6.96 MS (electrospray , + Ion) m / e 684 Example 8 trans-9- [4- [2-oxo-5-[[2- (2-pyridinyl) benzo
Yl] amino] -1,3,2-dioxaphospholinan-2-yl] butyl] -N
-(2,2,2-trifluoroethyl) -9H-fluorene-9-carboxami
Do hydrochloride A. 2- (2-pyridyl) benzoic acid A (1). 2-methyl-1- (2-pyridyl) benzene 2-bromopyridine (60 ml) in ethylene glycol dimethyl ether (60 ml)
1.9 ml (20 mmol) of the degassing solution under argon under tetrakis (triphenyl)
(Luphosphine) palladium (o) (700 mg, 0.6 mmol) is added. 1
After stirring for 0 minutes, 2-methylphenylboronic acid (2.9 g, 22 mmol) was added.
Then, a sodium bicarbonate solution (5.04 g, 60 mmol in 60 ml of water) was added.
I can. Heat the mixture to reflux (（85 ° C.) and stir overnight. After cooling to room temperature, the solvent
Evaporate, partition the residue between water and ether, and extract the aqueous layer twice with ether. Ko
Dry the combined organic layer (Na _Two SO _Four ) And evaporate the solvent to give a black oil
You. The oil was distilled at <1 torr and ~ 95 ° C to give the title compound (2.75 g, yield
82%) as a clear oil. A (2). Embedded image A (1) compound (850 mg, 5.0 mmol) in water (25 ml) and
And a solution of potassium permanganate (1.9 g, 12.0 mmol) was heated to reflux.
Stir for 1 hour. The warm reaction mixture is filtered and the filtrate is evaporated to dryness. Water solid residue
(5 ml) and acidify with acetic acid to pH 4-5. The resulting precipitate is filtered off
And rinsed with water to obtain a white solid (800 mg), which was recrystallized from warm ethanol.
To give the title compound as a white solid (453 mg, 45% yield). B. Trans-9- [4- [2-oxo-5-[[2- (2-pyridinyl) be
[Nzoyl] amino] -1,3,2-dioxaphospholinan-2-yl] butyl]
-N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxy
Samide hydrochloride 505 mg (0.82 mmol) of Example 6 compound in 10 ml of methanol
And 100 mg of 10% palladium / activated carbon slurry purged with argon
Is partially evacuated at room temperature and subjected to hydrogenation from a filling balloon. 4 hours later,
The mixture is purged with argon and filtered through a 0.45μ nylon filter. evaporation
Followed by re-evaporation from toluene to give a white foam. 10 ml of this substance
Of dichloromethane and stirred at room temperature under argon while 169 mg (0
. 83 mmol) of the above compound A, 162 mg (0.85 mmol) of EDCI
And 60 μl (0.43 mmol) of triethylamine are added. 16 hours later,
Saturated sodium bicarbonate solution was added to the reaction mixture to quench the reaction, and twice with ethyl acetate
Extract. Combine the organic extracts and dry (MgSO 4) _Four ) And evaporate. Flash on silica gel (5 × 15 cm column, methanol / ethyl acetate = 1: 24).
Purify by chromatography to obtain the free base of the title compound. This substance
Is dissolved in dichloromethane and treated with 0.3 ml of 4M hydrogen chloride / dioxane,
Evaporation gives the title compound as a white solid (mp 132-136 ° C, 524 mg, yield
Rate 81%). Microanalysis (C ₃₅ H ₃₃ F _Three N _Three O _Five P + HCl + dioxane + 0.25H _Two As O
) Calculated: C59.09, H5.40, N5.30, Cl4.47, F7.19.
, P3.91 Found: C59.12, H5.28, N5.24, Cl4.48, F7.37.
, P4.08 MS (electrospray, + ion) m / e 664 Example 9 trans-9- [4- [5-[[2- (2-benzothiazolyl) benzoyl]
Amino] -2-oxo-1,3,2-dioxaphospholinan-2-yl] butyl
] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carbo
Oxamide A. Embedded image The compound A is a commercially available compound supplied by Maybridge Chemical Company.
Be paid. B. Trans-9- [4- [5-[[2- (2-benzothiazolyl) benzoi]
[Amino] -2-oxo-1,3,2-dioxaphospholinan-2-yl] but
Tyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-ca
Luboxamide 371 mg (0.60 mmol) of Example 6 compound in 10 ml of methanol
And a slurry purged with 90 mg of 10% palladium / activated carbon with argon.
Partially evacuated at room temperature and subjected to hydrogenation from a full balloon. After 4h, reaction mixture
The material is purged with argon and filtered through a 0.45μ nylon filter. evaporation,
Then re-evaporation from toluene is performed to obtain a white foam. 5 ml of this substance
Dissolve in dichloromethane and stir at room temperature under argon while 153 mg (0.
. 60 mmol) of the above compound A, 114 mg (0.60 mmol) of EDCI
And 42 μl (0.3 mmol) of triethylamine are added. 16h later, anti
The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate.
Put out. Combine the organic extracts and dry (Na _Two SO _Four ) And evaporate. silica
Flash on gel (5 × 15 cm column, hexane / ethyl acetate = 1: 3)
Purify by chromatography to give the title compound as a white solid (mp 117-1).
18 ° C, 269 mg, yield 62%). Microanalysis (C ₃₇ H ₃₃ F _Three N _Three O _Five Calculated values: C61.75, H4.62, N5.84, F7.92, S4.45,
P4.30 Found: C62.02, H4.97, N5.55, F7.64, S4.06,
P4.42 MS (electrospray, + ion) m / e 720 Example 10 trans-9- [4- [5-[[2- (4-morpholinyl) benzoyl] amido
No] -2-oxo-1,3,2-dioxaphospholinan-2-yl] butyl]-
N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxa
Mido A. 2- (1-morpholino) benzoic acid A (1). Methyl 2- (1-morpholino) benzoate Methyl 2-fluorobenzoate in morpholine (44 ml, 500 mmol)
(15.4 g, 100 mmol) was heated at 50 ° C. for 30 min.
Heat to 0 ° C. and stir for 2 h, then cool to 50 ° C. and stir overnight. Reaction solution
Heat to reflux for 2.5 h. The excess morpholine is allowed to evaporate. Residue in ethyl acetate
Dissolved in H _Two O (50 ml), saturated NaHCO _Three Solution (50 ml × 2), H _Two Wash successively with O 2 (50 ml × 3) and brine (50 ml). Dry (MgSO _Four ) And evaporation to give a yellow oil. The crude product was treated with dichloromethane / ethyl acetate
Dissolved in toluene / hexane (4: 1: 4) and dissolved in 20-35% ethyl acetate / hexane.
Chromatography (400 g silica gel) eluting with a Tep gradient. pure
The fractions were combined and evaporated to give the title compound (10.5 g, 48%) as an oil.
This is allowed to crystallize on standing to give a white solid. A (2). 2- (1-morpholino) benzoic acid Dissolve sodium hydroxide (10 g, 250 mmol) in water (75 ml) and add
This was combined with the above compound A (1) (10.4 g, 47.1 ml) in methanol (75 ml).
Lmol). The reaction is stirred at RT for 1 h and the solvent is evaporated. White
Color residue H _Two Dissolve in O (100 ml) and adjust to pH 1.5 with 1N HCl. The aqueous layer is extracted with chloroform (250 ml × 3). Combined organic layer
Is dried (Na _Two SO _Four ) And evaporated to give the title compound (9.76 g, 85%) as a white solid.
Obtained in body (mp 156-157 ° C). B. Trans-9- [4- [5-[[2- (4-morpholinyl) benzoyl]
Amino] -2-oxo-1,3,2-dioxaphospholinan-2-yl] butyl
] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carbo
Oxamide 359 mg (0.582 mmol) of Example 6 in 15 ml of methanol
And 100 mg of 10% palladium / activated carbon slurry purged with argon
The vessel is partially evacuated at room temperature and subjected to hydrogenation from a full balloon. 16h later, anti
The reaction mixture is purged with argon and filtered through a 0.45μ nylon filter.
Evaporation followed by re-evaporation from toluene gives a white foam. This substance is 5
dissolved in dichloromethane and stirred at room temperature under argon, during which 121 m
g (0.584 mmol) of the above compound A, 88 mg (0.59 mmol) of H
OBt, 122 mg (0.64 mmol) of EDCI and 41 μl (0.3 ml)
Lmol) of triethylamine. After 6 h, the reaction mixture was charged with saturated sodium bicarbonate.
The reaction was quenched by addition of a solution of sodium hydroxide and extracted twice with ethyl acetate. Comb organic extract
And dried (Na _Two SO _Four ) And evaporate. Silica gel (5 × 20 cm column,
Purification by flash chromatography with ethyl acetate)
Obtained as a colored solid (mp 108-111 ° C., 265 mg, 66% yield). Microanalysis (C ₃₄ H ₃₇ F _Three N _Three O ₆ P + 0.15H _Two As O + 0.23 EtOAc
) Calculated: C60.38, H5.68, N6.05, F8.21 Actual: C60.37, H5.54, N5.93, F7.91 MS (electrospray, + ion) m / e 695. Example 11 trans-9- [4- [5-[[2- (2-benzoxazolyl) benzoyl]
Amino] -2-oxo-1,3,2-dioxaphospholinan-2-yl] butyl
] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carbo
Oxamide A. 2- (2-bromophenyl) benzoxazole 5.46 g (50.0 mmol) of 2-aminophen in 100 ml of xylene
(Aldrich) and 10.05 g (50.0 mmol) of 2-bromo
6.10 g (100 mmol) of stirred benzoic acid slurry at room temperature under argon
Of boric acid. The reaction is heated at reflux for 48 h using a Dean-Stark trap. Separate a total of 3.2 ml of water. Cool the reaction mixture
Cool, dilute with ethyl acetate and filter. The filtrate was saturated with 3M hydrochloric acid once and water once.
Wash three times with sodium bicarbonate solution. Dry the organic phase (MgSO _Four ) And evaporate. Silica gel (5 × 20 cm column, dichloromethane / hexane = 2: 1)
Purify by lash chromatography to obtain the title compound as a pale yellow solid (5
. 90 g, 43%). B. 2- (2-benzoxazolyl) benzoic acid Stirring 700 mg (2.55 mmol) of the above compound A in 10 ml of THF
The solution was added to a solution of t-butyllithium / pentane (1.7 M
, 3.3 ml, 5.6 mmol) over 30 minutes. 1 h of reaction mixture
Stir and then pass a dry gas stream of carbon dioxide through the solution for 1 h. Add the reaction solution to room temperature.
Warm up. After 16 h, the mixture was diluted with ether and 50 ml of 10% sodium hydroxide.
Wash once with an aqueous solution. The aqueous phase is adjusted to pH 3.5 with solid citric acid. can get
The solid is filtered off, washed with water and air dried to give 610 mg of the title compound as a pink solid
(Mp> 250 ° C., 100%). C. Trans-9- [4- [5-[[2- (2-benzoxazolyl) benzoi]
[Amino] -2-oxo-1,3,2-dioxaphospholinan-2-yl] but
Tyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-ca
Luboxamide 117 mg (0.24 mmol) of Example 6 compound in 3 ml of dichloromethane
72 mg (0.30 mmol) of the above B
Compound, 45 mg (0.3 mmol) HOBt, 65 mg (0.30 mmol)
Of EDCI and 20 μl (0.15 mmol) of triethylamine.
After 16 h, the reaction mixture was quenched with saturated sodium bicarbonate solution and acetic acid was added.
Extract twice with chill. Combine the organic extracts and dry (Na _Two SO _Four ) Then evaporate
I do. Silica gel (2.5 × 15 cm column, hexane / ethyl acetate = 1: 3)
Purify by flash chromatography at to obtain the title compound as a white solid
(Mp 104-107 ° C, 38 mg, 20% yield). Microanalysis (C ₃₇ H ₃₃ F _Three N _Three O ₆ P + 2.3H _Two (As O + 0.5 EtOAc) Calculated: C 59.36, H 5.31, N 5.32, F 7.22, P 3.92 Found: C 59.32, H 5.24, N 5.43, F 7.45, P 4.20 MS (Electrospray, + ion) m / e 704 Another alternative that can be made using the procedures described in the foregoing detailed description and Examples 1-11.
Specific examples of the compound of the present invention are represented by the following formula. The compound of the following formula is a cis-isomer
According to the invention, the corresponding trans-isomer is likewise according to the invention.
Protected. Embedded image Embedded image Embedded image Embedded image Embedded image

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 111 A61P 43/00 111 C07F 9/6574 C07F 9/6574 Z (81) Designated country EP (AT) , BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM) , GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, (KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, C Z, DE, DK, EE, ES, FI, GB, GE, GH, GM, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT , LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW F term (reference) 4C086 AA01 AA03 DA35 DA37 DA38 MA01 MA04 NA14 ZA45 ZA51 ZA66 ZA70 ZB11 ZC02 ZC33 ZC35 4H050 AA03 AB20 AB27

Claims (1)

[Claim 1] Formula: embedded image Wherein A is (1) a bond, (2) —O—, or Wherein R ⁵ is H or lower alkyl, or R ⁵ is taken together with R ² to form a 4- to 8-membered carbocyclic or heterocyclic group; B is of the formula: A fluorenyl-type group of the formula or B is of the formula: R ^a and R ^b are the same or different and are hydrogen, alkyl, aryl, arylalkyl, or heteroaryl bonded to the ring via a carbon atom; R ^5a is H, lower alkyl or aryl; R ¹ Is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, heteroarylalkoxy, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl , Cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, aryl Mino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all of which, optionally through an available carbon atom, are hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, Alkynyl, cycloalkyl,
Cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl,
Arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio , Heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
Alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
R ¹ and R ^5a may be substituted with 1, 2, 3 or 4 groups selected from arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl, or Together, the formula: Wherein J is of the formula , R ²³ , R ²⁴ and R ²⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, R ²⁰ , R ²¹ , R ²² is each independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl. Te, the substituents directly bonded to R ^1, or an open position may be bonded via an alkylene at; R ² is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, (alkyl or aryl) ₃ i (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl, heteroarylamino, Heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, cycloheteroalkyl, cycloheteroalkyl Alkyl, —PO (R ¹³ ) (R ¹⁴ ) wherein R ¹³ and R ¹⁴ are each independently
Alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy), cyano, 1,1- (alkoxy or aryloxy) ₂ alkyl wherein the two aryl or alkyl substituents can be independently defined, wherein R ² is any of the substituents for R ¹ above Or haloalkylamino, alkylamino, cycloalkylamino, arylamino, heteroarylamino, alkoxyamino, aryloxyamino, heteroaryloxyamino, heterocyclic amino (where the heterocyclic ring is a carbonyl group through a nitrogen or carbon atom. L ¹ is a bond containing from 1 to 10 carbons in a straight chain, including alkylene, alkenylene or alkynylene. A group of one or two alkenes in the linking chain,
It may contain one or two alkynes, oxygen, amino groups, oxo groups and
L ² may be the same as or different from L ¹ above, and L ² may independently be any of the above L ¹ groups or a single bond; R ³ , R ³ ′, R ⁴ and R ⁴ ′ are the same or different and are each independently H,
Halogen, CF ₃ , haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkyl Carbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar-, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, A
r-carbonyloxy or Ar-carbonylamino (where Ar is aryl or heteroaryl, and Ar may optionally contain one, two or three rings that are separately fused to Ar) R ^3a and R ^3b are the same or different and are each independently any of the above R ³ groups; Are the same or different and are each independently a 5- or 6-membered heteroaryl ring containing 1, 2, 3 or 4 heteroatoms (independently N, S or O) in the ring X also includes its N-oxide form; X is a bond, or a compound of the formula: It is either, where, Y is O, N-R ⁶ or S; n 'is 0, 1 or 2; R ⁶ is H, lower alkyl, aryl, -C (O) -R ¹¹ or - ^{C (O) -O-R 1} 1; R 7 and R ⁸ are the same or different, each, independently, H, alkyl, aryl, halogen or -O-R ¹² or R ⁷ and R ^8, together if R ⁹ , R ¹⁰ , R ⁹ ′ and R ¹⁰ ′ may be the same or different and each independently represent H
, Lower alkyl, aryl, or -O-R ^11; R ⁹ "and R ^10" are the same or different and each, independently, H, lower alkyl, aryl, halogen or -O-R ^11; R ¹¹ is alkyl or Aryl; R ¹² is H, alkyl or aryl, provided that when A is a (1) bond, R ² L ² must not be H], or a pharmaceutically acceptable salt thereof. Or N-oxide form. 2. The compound according to claim 1, wherein A is a bond. 3. The compound according to claim 1, wherein A is —O—. (4) A is The compound according to claim 1, which is 5. The compound according to claim 1, wherein B is a fluorenyl-type group. 6. The compound according to claim 1, wherein B is an indenyl type group. 7. A compound according to claim 6, wherein B is A is NH; X is a bond, oxygen or sulfur; R ³ and R ⁴ are the same or different; H or F; R ¹ is aryl, phenyl, biphenyl or cycloheteroalkyl; R ² is aryl, phenyl, heteroaryl , imidazolyl, pyridyl, ^{cyclohexyl, PO (R 13) (R} 14), heteroarylthio, benzthiazole-2
Thio, imidazol-2-thio, alkyl, alkenyl or 1,3-dioxan-2-a-yl, each of which may be optionally substituted; L ¹ is 1-5 atoms in a straight chain The compound according to claim 1, wherein L ² is a bond or a lower alkylene. 8. (E) -9- [4- [2-oxo-5-[[[4 ′-(trifluoromethyl) [1,1′-biphenyl] -2-yl] carbonyl] amino]- 1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoroethyl)
-9H-fluorene-9-carboxamide; (Z) -9- [4- [2-oxo-5-[[[4 '-(trifluoromethyl)-[1,1'-biphenyl] -2-yl] Carbonyl] amino] -1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide; trans-9- [ 4- [5- (benzoylamino) -2-oxo-1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoroethyl)-
9H-fluorene-9-carboxamide; trans-9- [5- [2-oxo-5-[[[4 '-(trifluoromethyl)-[1,
1'-biphenyl] -2-yl] carbonyl] amino] -1,3,2-dioxaphospholinan-2-yl] pentyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene -9-carboxamide; cis-9- [5- [2-oxo-5-[[4 '-(trifluoromethyl)-[1,1'-biphenyl] -2-yl] carbonyl] amino] -1 , 3,2-Dioxaphospholinan-2-yl] pentyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide; trans- [2-oxo-2- [4 -[9-[[(2,2,2-trifluoroethyl) amino] carbonyl] -9H-fluoren-9-yl] butyl] -1,3,2-dioxaphospholinan-5-yl] carbamic acid Trans-1- (phenylmethyl) -N- [2- [4- [9-[[(2,2,2-trifluoroethyl) amino] ca; Boniru]-9H-fluoren-9-yl] butyl] -1,
3,2-dioxaphospholinan-5-yl] -2-piperidinecarboxamide; trans-9- [4- [2-oxo-5-[[2- (2-pyridinyl) benzoyl] amino] -1,3 , 2-Dioxaphospholinan-2-yl] butyl] -N- (2,2,2
-Trifluoroethyl) -9H-fluorene-9-carboxamide; trans-9- [4- [5-[[2- (2-benzothiazolyl) benzoyl] amino]
-2-oxo-1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,
2,2-trifluoroethyl) -9H-fluorene-9-carboxamide; trans-9- [4- [5-[[2- (4-morpholinyl) benzoyl] amino] -2
-Oxo-1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide; trans-9- [4- [5-[[2- (2-benzoxazolyl) benzoyl] amino]
-2-oxo-1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,
The compound according to claim 1, which is (2,2-trifluoroethyl) -9H-fluorene-9-carboxamide or an ester or N-oxide thereof, or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, which is represented by the following formula: Embedded image 11. (E) -9- [4- [2-oxo-5-[[[4 '-(trifluoromethyl)-[1,1'-biphenyl] -2-yl] carbonyl] amino] -1,3,2-
Dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide; trans-9- [4- [5- (benzoylamino) -2 -Oxo-1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoroethyl)-
9H-fluorene-9-carboxamide; trans-9- [5- [2-oxo-5-[[[4 '-(trifluoromethyl)-[1,
1'-biphenyl] -2-yl] carbonyl] amino] -1,3,2-dioxaphospholinan-2-yl] pentyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene -9-carboxamide; trans- [2-oxo-2- [4- [9-[[(2,2,2-trifluoroethyl) amino] carbonyl] -9H-fluoren-9-yl] butyl] -1 , 3,2-dioxaphospholinan-5-yl] carbamic acid; trans-1- (phenylmethyl) -N- [2- [4- [9-[[(2,2,2-trifluoroethyl) Amino] carbonyl] -9H-fluoren-9-yl] butyl] -1,
3,2-dioxaphospholinan-5-yl] -2-piperidinecarboxamide; trans-9- [4- [2-oxo-5-[[2- (2-pyridinyl) benzoyl] amino] -1,3 , 2-Dioxaphospholinan-2-yl] butyl] -N- (2,2,2
-Trifluoroethyl) -9H-fluorene-9-carboxamide; trans-9- [4- [5-[[2- (2-benzothiazolyl) benzoyl] amino]
-2-oxo-1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,
2,2-trifluoroethyl) -9H-fluorene-9-carboxamide; trans-9- [4- [5-[[2- (4-morpholinyl) benzoyl] amino] -2
-Oxo-1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide; trans-9- [4- [5-[[2- (2-benzoxazolyl) benzoyl] amino]
-2-oxo-1,3,2-dioxaphospholinan-2-yl] butyl] -N- (2,
The compound according to claim 1, which is (2,2-trifluoroethyl) -9H-fluorene-9-carboxamide, an N-oxide thereof, or a pharmaceutically acceptable salt or ester thereof. 12. The compound according to claim 1, wherein A is NH and R ² L ² is CF ₃ CH ₂ . 13. A method for preventing, suppressing or treating atherosclerosis, pancreatitis, hyperglycemia or obesity in a mammal, comprising administering to a patient in need of such treatment,
A method comprising administering a therapeutically effective amount of a compound of claim 1. 14. A mammal that lowers serum lipid levels, cholesterol and / or triglyceride or reduces hyperlipidemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and / or hypertriglyceridemia. Suppression and / or
Or treating and / or preventing atherosclerosis, pancreatitis or obesity,
A method of inhibiting or treating, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1. 15. The method according to claim 14, wherein B is A is NH; X is a bond, oxygen or sulfur; R ³ and R ⁴ are the same or different; H or F; R ¹ is aryl, phenyl, biphenyl or cycloheteroalkyl; R ² is aryl, phenyl, heteroaryl , imidazolyl, pyridyl, ^{cyclohexyl, PO (R 13) (R} 14), heteroarylthio, benzthiazole-2
Thio, imidazol-2-thio, alkyl or alkenyl, 1,3-dioxan-2-yl, each of which may be optionally substituted; wherein L ¹ is linearly from 1 to 5 atoms The method according to claim 14, wherein L ² is a bond or a lower alkylene. 16. B is the following: X is a bond, oxygen or sulfur; R ³ and R ⁴ are the same or different and H or F; R ² is aryl, phenyl, heteroaryl, imidazolyl, pyridyl, cyclohexyl, PO (R ¹³ ) (R ¹⁴ ), hetero Arylthio, benzthiazole-2-
Thio, imidazole-2-thio, alkyl or alkenyl, 1,3-dioxan-2-yl, each of which may be optionally substituted; R ¹ is phenyl, biphenyl or piperidine; L ¹ is the method of claim 13 L ² is a bond or lower alkylene; chain containing 1-5 atoms in a straight chain.